US4547511A - Heterocyclic carboxamides, compositions containing such compounds, processes for their preparation and methods of treatment therewith - Google Patents

Heterocyclic carboxamides, compositions containing such compounds, processes for their preparation and methods of treatment therewith Download PDF

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US4547511A
US4547511A US06/350,890 US35089082A US4547511A US 4547511 A US4547511 A US 4547511A US 35089082 A US35089082 A US 35089082A US 4547511 A US4547511 A US 4547511A
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methyl
quinoline
dihydro
oxo
carboxamide
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Edgar Eriksoo
Eva B. Sandberg
Lars J. T. Stalhandske
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LEO A SWEDISH CORP AB
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Pfizer Health AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems

Definitions

  • This invention relates to novel heterocyclic carboxamides which increase the activity of the immune system and to the preparation thereof.
  • the invention is also concerned with pharmaceutical compositions containing the said compounds and methods of treatment therewith.
  • Certain heterocyclic carboxamides certain dihydro-1,4-disubstituted-quinoline-3-carboxylic acid amides; increasing the activity of the immune system; compounds per se, compositions thereof, methods of treating therewith.
  • the immune system of the body has long been the subject of concerted study.
  • a vigorous search has been made for drugs which influence the immune system.
  • Numerous drugs which suppress the activity of the immune system have been found and, more recently, some compounds have been discovered which increase the activity of the immune system of the body.
  • Some of these rather recently-discovered compounds have been found capable of increasing the activity of the cell-mediated immunity of the host.
  • the study of such compounds for such purpose is a branch of science which is still in its infancy, but of obviously great significance in view of the possibility of increasing immunity of a host by the administration of a drug.
  • the far-reaching effect of such research is apparent to all skilled in the art.
  • the compounds according to the present invention used for fundamentally different pharmacological purposes, do in fact, completely unexpectedly, increase the extent of carrageenan-induced edema in the test mentioned above (cf below and Table I of the present application), i.e. the compounds according to the present invention exhibit effects contrary to the effects exhibited by the previously known compounds.
  • Cell-mediated immunity is considered a major defence system against many infectious agents and neoplasms (1, 2).
  • Diseases such as rheumatoid arthritis and autoimmune disorders such as systemic lupus erythematosus are also attributed to impaired cell-mediated immunity.
  • Agents which can stimulate impaired cell-mediated immunity are consequently of great potential value in the treatment of the above-mentioned diseases.
  • An important expression of cell-mediated immunity is the delayed hypersensitivity reaction (1). An increase of this reaction therefore indicates enhanced cell-mediated immunity in the host (3).
  • a useful test for the evaluation of the effect of chemical compounds on the immune system is the pertussis vaccine pleurisy test in rats. Compounds which enhance the response in this delayed hypersensitivity reaction are considered to stimulate cell-mediated immunity (4).
  • the adjuvant arthritis test in rats produces a measureable extent of a delayed hypersensitivity reaction and can be used for a determination of variations in the extent of the delayed hypersensitivity reaction upon drug administration to the host. An increase in the extent of the delayed hypersensitivity reaction upon drug administration consequently indicates enhanced cell-mediated immunity in the host.
  • the new heterocyclic carboxamides of the present invention correspond to the general formula I as defined below.
  • the compounds of the invention have shown a potentiating effect in the carrageenan edema test in rat, in adjuvant arthritis in respect of the secondary symptoms, and in the pertussis vaccine pleurisy test.
  • the compounds of the invention can be employed in disorders responsive to treatment with agents which enhance cell-mediated immunity as such or combined with either solid or liquid carriers of diluents and made available in varying amounts in such pharmaceutical form as eg tablets, pills, capsules, pellets, powders, ointments, suppositories, aqueous or non-aqueous suspensions and solutions.
  • one object of the invention is to provide new compounds having the general formula I, having the aforesaid activity, preferably also with a low degree of toxicity.
  • a second object is to provide such type of compounds which can be employed in disorders, which are responsive to treatment with agents which enhance cell-mediated immunity, for the amelioration or palliation thereof.
  • Another object of the invention is to provide processes for preparing the new compounds having the general formula I.
  • a further object of the invention is to provide a method of treating a living animal body suffering from a disorder which is responsive to treatment with agents which enhance cell-mediated immunity, for the amelioration or palliation thereof, which comprises the step of administering to said living animal body a compound having the general formula I, said compound being administered in an amount sufficient to at least mitigate said disorder.
  • Yet another object of the invention is to provide compositions containing as an active ingredient one or more of the compounds having the general formula I, preferably together with a pharmaceutically acceptable carrier and, if desired, other pharmacologically active agents.
  • R 1 , R 2 and R 3 are the same or different and selected from the group consisting of: hydrogen; lower alkyl; lower alkoxy; halogen; NO 2 ; OH; OCOR 8 ; NR 6 R 7 ; and NR 6 COR 8 ; and where R 1 and R 2 or R 2 and R 3 together may also be in the from of a methylenedioxy group;
  • R 4 is selected from the group consisting of: lower alkyl; lower alkenyl; lower alkylene forming a ring with the 8-position carbon atom of the quinoline ring system; cycloalkyl, optionally mono- or disubstituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, OH, and OCOR 8 ; and phenyl, optionally mono- or disubstituted with substituents selected from the group consisting of lower alkyl, lower alkoxy and halogen, especially F, Cl, and Br; and
  • R 5 is selected from the group consisting of: a five- or six-membered heterocyclic ring containing at most two heteroatoms selected from the groups consisting of S, and N, and being optionally mono- or disubstituted; with substituents selected from the group consisting of lower alkyl, lower alkoxy, and halogen, especially F and Cl; and the group: ##STR2## wherein R 9 , R 10 , and R 11 are the same or different and selected from the group consisting of: hydrogen; lower alkyl; lower alkenyl; lower alkoxy; lower alkylthio; halogen; CN; SO 2 CH 3 ; OH; OCOR 8 ; NR 6 R 7 ; NR 6 COR 8 ; COOR 12 ; OCH 2 COOR 12 ; CH 2 COOR 12 ; COR 8 ; and ##STR3## wherein m is four or five; and where R 9 and R 10 or R 10 and R 11 together also may be in the form of a methyl
  • a 1 is selected from the group consisting of OR 12 , OCOR 8 , NR 6 R 7 and NR 6 COR 8 and A 2 is selected from the group consisting of O and NR 6 ;
  • R 6 and R 7 are selected from the group consisting of hydrogen and lower alkyl; wherein R 8 is lower alkyl; wherein R 12 is selected from the group consisting of lower alkyl and M; and where M is selected from the group consisting of hydrogen and pharmaceutically acceptable inorganic and organic cations; and
  • R 13 is selected from the group consisting of hydrogen, lower alkyl, optionally substituted with a substituent selected from the group consisting of OH, OR 8 and OCOR 8 , and lower alkenyl; provided that R 13 is selected from the group consisting of lower alkyl, optionally substituted with a substituent selected from the group consisting of OH, OR 8 and OCOR 8 , and lower alkenyl when R 9 , R 10 and R 11 are selected from the group consisting of lower alkyl, lower alkenyl and lower alkoxy.
  • the compounds of the present invention which contain salt-forming basic nitrogen atoms may also be in the form of addition salts with pharmaceutically acceptable inorganic or organic acids, the salts thus formed being such as the hydrochlorides, hydrobromides, phosphates, nitrates, sulphates, hydrogenoxalates, oxalates, succinates, tartrates, methanesulphonates, and ethanedisulphonates.
  • lower alkyl, lower alkenyl, lower alkylene, lower alkoxy, and lower alkanols include for instance: methyl, ethyl, propyl, iso-propyl, butyl, secondary butyl, iso-butyl, tertiary butyl, vinyl, iso-propenyl, 1-propenyl, allyl, ethylene, trimethylene, propylene, tetramethylene, 1,2-dimethylethylene, ethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, methanol, ethanol, propanol, isopropanol, butanol, iso-butanol, secondary butanol, and tertiary butanol.
  • metals calcium, potassium, and sodium
  • amines monoethanolamine, diethanolamine, dimethylaminoethanol, N-methylglucamine, trihydroxymethylmethylamine, morpholine, and the like.
  • substituents R 1 , R 2 , and R 3 it is preferred that these substituents are hydrogen, lower alkyl, lower alkoxy, halogen, OH, OCOR 8 , NR 6 R 7 , and methylenedioxy.
  • R 1 , R 2 , and R 3 are halogen or NR 6 R 7 it is preferred that only one of R 1 , R 2 , and R 3 consists of one of said substituents.
  • R 1 , R 2 , or R 3 is F, Cl, or Br, especially F and Cl.
  • R 4 is lower alkyl.
  • R 4 is a lower alkyl group a methyl group is preferred.
  • R 4 is lower alkylene forming a ring with the 8-position carbon atom of the quinoline ring system such types of compounds have a stable configuration and are therefore of special interest, whereby ethylene and trimethylene groups are preferred as the lower alkylene groups.
  • R 4 is substituted phenyl, monosubstitution in p-position is preferred.
  • R 4 is cycloalkyl
  • cyclopentyl and cyclohexyl are preferred and, if the cycloalkyl ring is substituted, monosubstitution is preferred.
  • R 5 is the group II above it is preferred that at least one of the substituents R 9 , R 10 , and R 11 is hydrogen and, when two of said substituents are hydrogen, it is also preferred that the remaining substituent is situated in the p-position.
  • R 5 is a five- or six-membered heterocyclic ring, and the heterocyclic ring contains two heteroatoms of the same kind, N is preferred.
  • R 5 is a heterocyclic ring
  • the following heterocyclic ring systems are of special interest in the present invention:
  • R 5 is a substituted heterocyclic ring monosubstitution is preferred.
  • a 1 is OR 12 or OCOR 8 it is preferred that A 2 is O.
  • a 1 is NR 6 R 7 or NR 6 COR 8 it is preferred that A 2 is O.
  • a 2 is NR 6 it is preferred that A 1 is OR 12 or OCOR 8 .
  • R 12 is M.
  • R 12 is a lower alkyl group
  • methyl and ethyl groups are preferred.
  • M is an inorganic cation
  • potassium and sodium ions are preferred.
  • R 5 is the above group II.
  • R 13 is lower alkyl, optionally substituted with a substituent selected from OH, OR 8 or OCOR 8 , or lower alkenyl, especially lower alkyl.
  • R 13 is lower alkyl, optionally substituted with a substituent selected from OH, OR 8 or OCOR 8 , or lower alkenyl it is preferred that one of the substituents R 9 , R 10 , and R 11 is lower alkyl, lower alkoxy or halogen, especially F and Cl.
  • R 13 is hydrogen it is preferred that one of the substituents R 9 , R 10 , and R 11 is halogen, OH, OCOR 8 , NR 6 R 7 , NR 6 COR 8 , COOR 12 , OCH 2 COOR 12 , CH 2 COOR 12 or ##STR5##
  • R 13 is hydrogen it is also preferred that one of the substituents R 9 , R 10 and R 11 is a group which confers water solubility to the compound hereby obtained.
  • R 13 is lower alkyl, optionally substituted with a substituent selected from OH, OR 8 or OCOR 8 , or lower alkenyl it is also preferred that A 1 is OH, A 2 is O, R 4 is lower alkyl and R 5 is the group II as defined above.
  • R 13 is hydrogen it is also preferred that R 4 is lower alkyl and R 5 is a heterocyclic ring.
  • a 1 is NR 6 R 7 or NR 6 COR 8 it is preferred that A 2 is O, R 4 is lower alkyl and R 5 is the group II as defined above.
  • the above compounds may also be in the form of salts with pharmaceutically acceptable inorganic or organic cations or addition salts with pharmaceutically acceptable inorganic or organic acids.
  • the compounds having the general formula I may be prepared by conventional methods.
  • a reactive derivative of a dicarboxylic acid IV is reacted with an amine ##STR8## to form compounds of the general formula I, wherein A 1 is OH and A 2 is O.
  • a compound of the general formula IX ##STR10## wherein X is halogen, preferably Cl or Br, is reacted with a compound A 1 H or a reactive derivative thereof to form compounds of the general formula I, wherein A 2 is O.
  • the reaction may be carried out by mixing the reagents in an inert solvent medium at a temperature between 0° and 200° C. depending on the reactivity of the reactive derivative of the carboxylic acid III used.
  • reactive derivatives the following conventional types may be mentioned: lower alkyl esters (preferably methyl or ethyl esters), anhydrides, acid chlorides, mixed anhydrides with aliphatic or aromatic sulphonic acids, and reactive derivatives obtained with carbodiimides and similar reagents.
  • Pyridine and quinoline are especially suitable as inert solvents.
  • the carboxylic acids III and reactive derivatives thereof may be prepared by conventional methods as described in (6).
  • lower alkyl esters of the carboxylic acid III may be prepared by the method described in (7).
  • the amines R 5 R 13 NH are known compounds or can be prepared by conventional methods as described in (8).
  • the process according to method I may also be carried out by reacting the carboxylic acid III with a reactive derivative of the amine R 5 R 13 NH.
  • Such reactive derivatives may be compounds formed by mixing the amine R 5 R 13 NH with a phosphorous compound such as phosphorous trichloride.
  • the reaction may be carried out by mixing the reagents in an inert solvent medium and heating at a temperature between 0° C. and the boiling point of the reaction mixture.
  • a process according to method 2 characterized by reacting a reactive derivative of a dicarboxylic acid IV with an amine V.
  • the reaction may be carried out by mixing the reagents in an inert solvent medium and heating at a temperature above 100° C., preferably between 150° and 250° C.
  • methyl, ethyl, or phenyl esters may be used as reactive derivatives of the dicarboxylic acid IV .
  • Diphenyl ether is a suitable solvent for the process.
  • the reactive derivatives of the dicarboxylic acid IV are known compounds or can be prepared according to the general method described in (9).
  • the amines V are known compounds or may be prepared by conventional methods as described in (8).
  • alkali alkoxides such as sodium methoxide and sodium hydride.
  • the reaction is preferably carried out in an inert solvent such as dimethylformamide, or in a solvent which is also a proton acceptor such as pyridine or quinoline.
  • an inert solvent such as dimethylformamide
  • a solvent which is also a proton acceptor such as pyridine or quinoline.
  • the reaction is preferably carried out above room temperature, preferably between 50° and 150° C.
  • the starting materials VI are known compounds or may be prepared by methods described in (10).
  • the lower alkyl esters of the acid VII are known compounds or may be prepared by using the general method described in (11).
  • nitrile VIII When the nitrile VIII is used in this process a compound I wherein A 1 is OH and A 2 is NH is obtained.
  • the nitriles VIII are known compounds or may be prepared by using known methods.
  • a process according to method 4 characterized by converting the halogen substituent X in compound IX to a group A 1 may be carried out by using conventional methods.
  • One such method is a reaction of IX with aqueous solutions of hydroxides of sodium or potassium between room temperature and the boiling point of the reaction mixture.
  • Another method is reacting the compound IX with an alkali salt of an alkanoic acid, preferably in an aprotic dipolar solvent such as dimethylformamide, dimethylacetamide, or dimethyl sulphoxide followed by hydrolysis. Both these methods give compounds I wherein A 1 is OH.
  • a compound I wherein A 1 is OR 12 , wherein R 12 is lower alkyl may be produced by reacting a compound IX with a compound containing a reactive alkoxide ion such as an alkali lower alkoxide.
  • the reaction is preferably carried out in an inert solvent medium between room temperature and the boiling point of the reaction mixture.
  • a compound I wherein A 1 is NR 6 R 7 is desired, this may be produced by reacting a compound IX with an amine NR 6 R 7 H.
  • the reaction is preferably carried out in an inert solvent medium between room temperature and 200° C. The reaction may if necessary be carried out under pressure.
  • the starting materials of the formula IX may be prepared by the general method illustrated in Example 4 below.
  • All the above processes, a-d, may optionally be carried out in the presence of a catalyst known to be useful in said processes.
  • Free hydroxy groups are, e.g., obtained by removal of acyl groups from carboxylic esters or by removal of lower alkyl groups from lower alkoxy groups.
  • Free amino groups are, e.g., obtained by removal of acyl groups from carboxamides or by reduction of nitro groups.
  • Free carboxylic acid groups are, e.g., obtained by hydrolysis of ester-, amide-, and nitrile groups.
  • free hydroxy groups can be esterified and etherified, primary and secondary amines acylated to amides, and carboxylic acids esterified.
  • each group of the starting materials involved must be compatible with the process is question or, if necessary, protected during one or more reaction steps and then converted to the desired group.
  • Pertinent examples of groups that may be protected are hydroxy-, carboxyl-, and primary and secondary amino groups. Examples of such protecting groups are found in (14).
  • the compounds of the invention are generally characterized by the pharmacological activity hereinbefore stated, making them useful in counteracting certain physiological abnormalities in a living animal body.
  • Effective quantities of the pharmacologically active compounds of the invention may be administered to a living animal body in any one of various ways, for example orally as in capsules or tablets, parenterally in the form of sterile solutions, suspensions, and by pellet implantation.
  • routes of parenteral administration are intravenously, subcutaneously, intramuscularly, intraperitoneally, intraarticularly, and intradermally.
  • Other modes of administration are vaginally, rectally, and topically as, e.g., in the form of ointments, suppositories, and powders.
  • compositions are usually prepared from a predetermined quantity of one or more of the compounds of the invention.
  • Such formulations may take the form of powder, syrups, suppositories, ointments, solutions, pills, capsules, pellets or tablets, suspensions, emulsions, oil solutions, etc, with or without, but preferably with, any one of a large variety of pharmaceutically acceptable vehicles or carriers.
  • the active ingredient When in a mixture with a pharmaceutical vehicle or carrier, the active ingredient usually comprises from about 0.01 to about 75 percent, normally from about 0.05 to about 15 percent, by weight of the composition.
  • Carriers such as starch, sugar, talc, commonly used synthetic and natural gums, water, and the like, may be used in such formulations.
  • Binders such as polyvinylpyrrolidone and lubricants such as sodium stearate, may be used to form tablets.
  • Disintegrating agents such as sodium carbonate may also be included in tablets.
  • unit dosages are preferably five milligrams or above and preferably twenty-five, fifty, or one hundred milligrams, or even higher, depending of course upon the subject treated and the particular result desired, as will be apparent to one skilled in the art. Broader ranges appear to be 1 to 1000 milligrams per unit dose.
  • the active agents of the invention may be combined for administration with other pharmaceutically active agents such as analgesics, steroids or hormones, or the like, or with buffers, antacids, or the like, and the proportion of the active agent or agents in the compositions may be varied widely. It is only necessary that the active ingredient of the invention constitutes an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. The exact individual dosage as well as daily dosages in a particular case will of course be determined according to well established medical and/or veterinary principles under the supervision of the physician or veterinarian in charge.
  • the present compounds when used therapeutically, may be administered in a quantity of 1 to 1000 milligrams, preferred ranges being 5-250 milligrams per day and subject or patient, divided in 1 to 4 or more doses, over a suitable period and depending upon the subject and the type of subject being treated.
  • N-phenylcarbamoyl-dimethylmalonate 14 parts
  • 4-methoxy-N-methyl-aniline 7 parts
  • the methanol formed is distilled off continuously.
  • the reaction mixture is poured into warm acetic acid, and the product, N-phenyl-1,2-dihydro-4-hydroxy-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide (1) (the same compound as 1:2), precipitates and is filtered off.
  • a mixture of 65 parts of 1,2-dihydro-4-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester, 17.3 parts of 63% aqueous hydrobromic acid, and 36.3 parts of acetic anhydride is heated at 65° C. for 4 h and then left overnight at room temperature.
  • the crystals formed are filtered off and then dissolved in aqueous sodium hydroxide solution and extracted with methylene chloride.
  • the aqueous phase is acidified.
  • the crystals of 1,2-dihydro-4-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid precipitate are filtered off and dried. M. p. 228° C.
  • a mixture containing one part of each of anhydrous sodium acetate, dimethylformamide, and N-phenyl-4-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide is heated at 150° C. for 3 h.
  • the reaction mixture is cooled to room temperature, aqueous hydrochloric acid is added, and thereafter extracted with ethyl acetate. From the extract is obtained after evaporation to dryness and crystallization from pyridine N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (1) (the same compound as 1:1).
  • N-phenyl-1,2-dihydro-4-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide prepared according to Example 6
  • 5 parts of 5 molar aqueous hydrochloric acid is refluxed for 2.5 h, cooled to room temperature and then neutralized with aqueous sodium hydroxide solution.
  • the crystalline product obtained is filtered off and recrystallized from pyridine to give N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (1) (the same compound as 1:1).
  • the precipitate formed is filtered off and dissolved in water.
  • the aqueous solution is washed with methylene chloride and then acidified with aqueous hydrochloric acid.
  • the precipitate formed consists of 1,2-dihydro-4-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid. M. p. 177° C.
  • reaction mixture is allowed to warm up to room temperature and is then extracted with water and aqueous sodium hydrogen carbonate solution.
  • the chloroform solution is evaporated to dryness in vacuo, and the residue is crystallized from butanone to give N-phenyl-1,2-dihydro-4-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide (1).
  • a reaction mixture consisting of N-phenyl-4-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (12 parts), concentrated aqueous ammonia (25 parts), and methanol (60 parts) is heated in an autoclave at 100° C. for 48 hours. After cooling to room temperature the precipitate formed is filtered off and recrystallized from pyridine and dried to give N-phenyl-4-amino-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (1). M. p. 248° C.
  • a reaction mixture consisting of N-methyl-isatoic anhydride (18 parts), N-phenyl-cyano-acetamide (18 parts), pyridine (100 parts), and triethylamine (10 parts) is stirred at room temperature for five days. Water is added and the precipitate formed is removed by filtration. The filtrate is acidified and extracted with methylene chloride. After drying and evaporation to dryness in vacuo the extract gives a crystalline residue which consists of N-phenyl-1,2-dihydro-4-hydroxy-2-imino-1-methyl-quinoline-3-carboxamide (1). M. p. 275°-277° C.
  • the crystalline precipitate is filtered off and washed with water, methanol, and ethyl ether and consists of N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide sodium salt (1).
  • Example 6 The general method described in Example 6 above is used for the preparation of the following compounds from the corresponding starting materials.
  • Example 6 The general method described in Example 6 above is used for the preparation of the following compounds from the corresponding starting materials.
  • Example 6 The general method described in Example 6 above is used for the preparation of the following compounds from the corresponding starting materials.
  • the reaction mixture is then heated at 110° C. while stirring under vacuum for 40 minutes. Water is added after cooling to room temperature, and the solution so obtained is extracted with ethyl ether.
  • the aqueous phase is acidified with hydrochloric acid solution and extracted with methylene chloride.
  • the extract is washed with water, dried and evaporated to dryness.
  • the crystalline residue is washed with acetone and, dried, consists of N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-2-oxo-1,8-trimethylene-quinoline-3-carboxamide (1). M. p. 234° C.
  • Phosphorous trichloride (1.73 parts) is added dropwise to a solution of 8.1 parts of N-methylaniline in 40 parts to dry toluene while stirring the reaction mixture. Stirring is continued at room temperature for 30 minutes, whereafter 6.15 parts of 1,2-dihydro-4-hydroxy-1-allyl-2-oxo-quinoline-3-carboxylic acid are added. The reaction mixture is heated at 100° C. for two hours and then cooled down.
  • reaction mixture is extracted with a 2M sodium hydroxide solution and the extract obtained is neutralized and clarified by filtration.
  • the filtrate is acidifed and the precipitate formed is filtered off and dissolved in methylene chloride and the solution is clarified by filtration and evaporated to dryness. The crystalline residue is washed with acetone and dried.
  • the product so obtained consists of N-methyl-N-phenyl-1,2-dihydro-1-allyl-4-hydroxy-2-oxo-quinoline-3-carboxamide, (1). M. p. 204° C.
  • the ethylester (1) described above (3,4 parts) is dissolved in a solution consisting of acetic acid (14,3 parts) and 63% aqueous hydrobromic acid (5,8 parts).
  • the solution so obtained is heated at 120° C. for 20 minutes. After standing over night at room temperature a crystalline precipitate is formed which is filtered off. The crystals are reprecipitated by dissolving in aqueous alkali and acidification to give 1,2-dihydro-1,8-ethylene-4-hydroxy-2-oxo-quinoline-3-carboxylic acid (2).
  • N,N-dicyclohexylcarbodiimide (2,6 parts) is added to a mixture consisting of 1,2-dihydro-1,8-ethylene-4-hydroxy-2-oxo-3-carboxylic acid (2) (2,3 parts), N-methylaniline (1,1 parts) and dry toluene (20 parts) while stirring. Thereafter the stirring is continued at 90° C. for one hour.
  • the reaction mixture is cooled to room temperature and the precipitate formed is filtered off.
  • the precipitate is extracted with 2M sodium hydroxide solution.
  • the extract is neutralized and clarified by filtration and acidified with hydrochloric acid solution and then extracted with methylene chloride.
  • the methylene chloride extract is dried and evaporated to dryness in vacuum.
  • This example illustrates the effect of the compounds of the general formula I in the carrageenan edema test in rats.
  • a modification of a method described in (5) was used.
  • Female Sprague-Dawley rats weighing 110-120 g were used. At least 10 animals were used in each experimental group. Foot edema was induced by injecting carrageenan in 0.9% NaCl into the plantar surface of the right hind paw of the rats.
  • the substances suspended in aqueous methocel solution 10 ml/kg were administered intragastrically 30 minutes before the injection of carrageenan.
  • the control groups were given methocel solution 10 ml/kg.
  • This example illustrates the effect of the compounds of the general formula I in the adjuvant arthritis test in rats.
  • the adjuvant arthritis test in rats produces a delayed hypersensitivity reaction and can be used for a determination of variations of the delayed hypersensitivity reaction upon drug administration to the host.
  • An increase in the extent of the delayed hypersensitivity reaction upon drug administration consequently indicates enhanced cell-mediated immunity in the host.
  • the substances suspended in aqueous methocel solution 10 ml/kg were given intragastrically.
  • the control group was given methocel solution 10 ml/kg.
  • the different groups of animals were thus treated once daily from day -4 to day 14.
  • the effect of the substances was assessed by the left foot volume expressed in percent after comparison with the control groups.
  • the following additional compounds have a significant potentiating effect in the adjuvant arthritis test in rats in a dose of 40 mg/kg p.o.: 1:2, 1:9, 1:10, 1:12, 1:19, 1:22, 13:3, 21:4, 21:5, 21:7, 21:11, 21:14, 21:17, 21:19, 21:23, 21:24, 21:26, 21:28, 21:30, 21:31, 21:33, 21:35.
  • the toxicity of the compounds of the general formula I is low.
  • the LD50 values which have been determined in mice p. o. are higher than 1000 mg/kg.
  • mice The acute LD50 of levamisole in mice is 285 mg/kg p. o. (13).
  • Pertussis vaccine pleurisy is a useful test for the evaluation of the effect of chemical compounds on the immune system. Compounds which enhance the response in this delayed hypersensitivity reaction are considered to stimulate cell-mediated immunity.
  • Equal volumes of Freund's incomplete adjuvant and a suspension of heat killed Bordetella pertussis organisms were mixed.
  • day 0 0.2 ml of a mixture containing 0.036 ⁇ 10 10 organisms/ml was injected into the dorsal surface of one hind paw and one forepaw.
  • the animals were challenged on day 12 with 0.1 ml of a mixture containing 0.25 ⁇ 10 10 organisms/ml that was injected intrapleurally. 48 hours after challenge, day 14, the volume of the exudate in the pleural cavity was measured.
  • the substances suspended in aqueous methocel solution 10 ml/kg were given intragastrically once daily from day 10 to day 13.
  • the control groups were given methocel solution 10 ml/kg.
  • the substances are mixed and filled in capsules.
  • the substances are dissolved in distilled water.
  • the solution is dispensed in vials and freeze-dried.
  • the Active Compounds are those covered by the general formula I above or their addition salts with pharmaceutically acceptable inorganic or organic acids.
  • Watersoluble Active Compounds are such addition salts or salts with a pharmaceutically acceptable inorganic or organic cations.
  • Those Active Compounds which are disclosed in the foregoing Examples 1-21 are preferred as Active Compounds as such or in the form of their salts.
  • two or more Active Compounds of the invention may be used in combination in the compositions illustrated, and also, if desired, in combination with other pharmacologically active agents.

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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
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NO163130B (no) 1990-01-02
NO820642L (no) 1982-09-06
ES8400409A1 (es) 1983-10-16
PT74512B (en) 1983-11-08
US4738971A (en) 1988-04-19
KR860001876B1 (ko) 1986-10-24
JPH049786B2 (enrdf_load_stackoverflow) 1992-02-21
JPS57171975A (en) 1982-10-22
EP0059698A1 (en) 1982-09-08
KR830009037A (ko) 1983-12-17
NZ199888A (en) 1985-07-31
CA1182455A (en) 1985-02-12
ATE15798T1 (de) 1985-10-15
DK157859B (da) 1990-02-26
IE820314L (en) 1982-09-03
FI79532C (fi) 1990-01-10
ES510042A0 (es) 1983-10-16
AU8107682A (en) 1982-09-09
ZA821210B (en) 1983-01-26
DK157859C (da) 1990-07-30
IL65028A0 (en) 1982-04-30
AU547849B2 (en) 1985-11-07
HK38689A (en) 1989-05-19
HU186909B (en) 1985-10-28
FI79532B (fi) 1989-09-29
IL65028A (en) 1986-11-30
EP0059698B1 (en) 1985-09-25
GR76073B (enrdf_load_stackoverflow) 1984-08-03
PH18520A (en) 1985-08-02
FI820728L (fi) 1982-09-04
DE3266464D1 (en) 1985-10-31
PT74512A (en) 1982-04-01
NO163130C (no) 1990-04-11
IE52670B1 (en) 1988-01-20
DK81282A (da) 1982-09-04

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